HIV gp41 is a heavily glycosylated transmembrane protein. The difficulty in producing full length recombinant gp41 requires an incremental approach for structural determination. The ectodomain region, located on the outer surface of the viral membrane directly mediates membrane fusion events via an N-terminal fusion domain. In previous work both the NMR and X-ray structures of the gp41 ectodomain were determined. Both methods indicated a rod-like trimer comprising three parallel N-terminal alpha-helices assembled as a coiled-coil in the center with three antiparallel C-terminal alpha-helices packed on the outside with highly flexible loops connecting the inner and outer helices (6-helical bundle). In 2005 we reported the structure of fusion domain which consists of an N-terminal helix with a C-terminal linker region. To understand in more detail the interaction between the fusion domain, and the rest of the ectodomain, constructs which included the following domains: N-terminal fusion domain - 6 helical bundle -linker region - transmembrane region. This complex protein which contains two membrane associating domains was expressed in bacteria and purified as a protein-detergent complex. The protein was shown to be physical homogenous and readily formed crystals. To improve the quality of the crystals for high-resolution X-ray analysis we are screening the detergents which maintain the solubility of the protein acting as surrogate membranes. In additional, we have used the protein for immunizations and have initiated functional studies of protein reconstituted into lipid bilayers. It is hoped that the structural, biochemical and immunological studies will provide some insight to how the fusion and the transmembrane domain interact. This information is directly related to development of a better understanding of the mechanism of viral membrane fusion.